Applicant

 Name: Univ.-Prof. Dr. Arndt F. Schilling

 E-mail: arndt.schilling@med.uni-goettingen.de


Cartilage Adjacent Subchondral Bone (CASB) in ageing and disease as a diagnostic and therapeutic target

Careful evaluation of animal experimental data of osteoarthritis (OA) has revealed that changes in the subchondral bone structure precede the loss of cartilage. These results suggest that the increased bone mass in the subchondral zone may also be a cause rather than only an effect of OA. In this project we will specifically study at ultra-high resolution the zone between the cartilage and the spongy bone consisting of tidemark, calcified cartilage and subchondral bone, which we will term cartilage adjacent subchondral bone (CASB). In healthy joints, this complicated structure is reported to gradually relay impacting forces from the soft cartilage to the hard spongy bone.

 

Our working hypothesis is that the three-dimensional nano-architecture of the cartilage adjacent subchondral bone (CASB), changes during the development of OA. We further hypothesize that these changes play an important role in the development of osteoarthritis and can be utilized for the development of early diagnostic tools, for the monitoring of treatment and the development of novel therapeutic strategies.

 

Consequently, our main objective is it to investigate the 3D-nano-architecture of the CASB in healthy and osteoarthritic samples, correlate observed changes in the bone to changes in the cartilage and develop theories to explain our findings and propose novel diagnostics and treatment modalities.

 

To reach these objectives we will follow 6 specific aims:

We will study the physiologic development of the nano-architecture of the CASB in animal models (Aim 1). New tools will be developed to enhance visualization and analysis of CASB 3D-data through 3D-printing and Virtual Reality (VR) imaging (Aim 2). Changes in the nano-architecture of the CASB will be analyzed in animal models of OA-pathology (Aim 3). The CASB will be studied in human samples of OA (Aim 4). Based on the data collected in Aim 1-4 we will evaluate diagnostic and treatment options (Aim 5) and will develop a new model of cartilage-CASB interaction (Aim 6).



Key Achievements of the First Funding Period

Figure legend:

Cartilage adjacent subchondral bone in aging and disease. (A) Histological and nano-CT analyses indicate changes in bone parameters during aging of the bovine medial condyle of the femur. C, cartilage; CC, calcified cartilage; SCBP, subchondral bone plate. (B) 3D reconstructed images in the SB zone reveals that microchannels reach the cartilage and are more frequent and smaller in size in calf compared with cattle. (C) The bone material properties were age and location dependent.

 

 

The non-calcified articular cartilage (AC), the calcified cartilage (CC) and the cortical and trabecular subchondral bone (SB) in the joint form a bio-composite that is uniquely adapted for load dissipation. Within ExCarBon, we have hypothesized that the calcified cartilage and the SB, termed cartilage adjacent subchondral bone (CASB), harbours a distinct 3D-microarchitecture that is correlated with the overlying cartilage during physiological joint development, OA initiation and progression (SP5). As supporting evidence, we have demonstrated a developmental transformation of connective cavities within the CASB of the medial femoral condyle during bovine joint maturation using high-resolution nanoCT, histomorphometry and scanning electron element analysis. We found that the number of trabeculae and their connectivity increases as the region shifts from calcified cartilage to the subchondral bone plate (Fig. 1A). A series of intricate microchannel structures connected the subchondral trabecular bone to the tidemark, which were more frequent and smaller in calves compared to cattle (Fig. 1B) and the material properties of the surrounding bone changed in relation to distance from the tidemark (Fig. 1C). This methodology was adapted for use in the different animal models of OA development of the consortium, showing specific changes in the different layers of the CASB. We have developed a workflow that now enables us to study the CASB as 3D-print, as well as in virtual reality (VR) and augmented reality (AR) for better visualization and analysis of the structures. To translate these methodologies to human bones, human femoral heads were collected and graded according to the Outerbridge classification by orthopaedic surgeons and then analysed according to their physiological biomechanical loading. We found strong location-dependent differences in SB microarchitecture. Our data quantifies a so far elusive location- and disease-state dependent microarchitecture that is correlated with the overlying cartilage and the loading state of the respective location and therefore may qualify as a new target for diagnostics and treatment.